Camptothecin is an alkaloid isolated by Wall et al. (J. Am. Chem. Soc., 88, 3888-3890 (1966)) for the first time from the tree Camptotheca acuminata, a plant native to China, belonging to the Nyssaceae family. The molecule consists of a pentacyclic structure with a lactone in the E ring, which is essential for cytotoxicity.
For a review of the camptothecins and the problems relating to their use as medicaments, as well as the resolution of a number of such problems, see European Patent EP 1044977, filed in the name of the applicant.
As regards the problem of the lactone ring, which is a portion of the molecule essential for the camptothecins to be able to exercise their pharmacological activity, one aspect which has yet to be fully resolved is the stability of the ring itself, which, in turn, is responsible for the half-life of the drug.
Patent application WO 97/00876, filed in the name of Societè de Conseils de Recherches et d'Applications Scientifiques, and published on Jan. 9, 1997, describes camptothecins in which the lactone ring has been modified from its original α-hydroxylactone structure to a β-hydroxylactone structure (homocamptothecins), bringing the lactone cycle up from six to seven members. These compounds inhibit topo-isomerase I DNA relaxation activity and are endowed with cytotoxic activity against several tumour lines. The β-hydroxylactone structure is defined as a lactone that involves the presence of a supplementary carbon atom between the carboxyl carbon atom and the carbon atom in α-bearing the hydroxy in the α-hydroxylactone structure. To increase the stability of the lactone ring, the inventors suggest substituents on the supplementary carbon atom, and the substituents indicated are the lower alkyls together with the lower alkoxy, halogen or hydroxy. In the patent application mentioned no evidence of improved stability of the lactone ring is provided. In a subsequent patent application, WO 98/28304, published on Jul. 2, 1998, the same applicant describes further camptothecins with a β-hydroxylactone structure, where the hydroxy group is functionalised with groups that are capable of restoring it in vivo, thus effectively furnishing prodrugs of the molecules described in the preceding patent application, and also resolving the problem of the severe side effects of products in the present state of the art. In this case, too, no experimental evidence is provided that the technical problem has been solved. In J. Med. Chem., 1998, Vol 41, No 27, 5410-5419, the same inventors as in the abovementioned patent applications indicate the lactone in position 7, therein described, as an instrument for increasing the stability of the lactone ring, and thus as a useful model for elaborating further camptothecin derivatives. See also Bioorg. Med. Chem. Lett., 9, (1999) 2599-2602; Biochemistry, 1999, 38, 15556-15563; Cancer Research, 59 2939-2943. Other modifications of homocamptothecin on the A and B rings are described in WO 00/61146, University of Pittsburgh et al., published on Oct. 19, 2000, and in J. Med. Chem., 1999, 42, 3018-3022 for the so-called “homosilatecans”, which are potent, stable topo-isomerase I inhibitors. Homocamptothecins with further modifications are described in J. Med. Chem., 2000, 43, 2285-2289, Anti-cancer Drug Design, (2001), 12, 9-19, where the anticancer activity is increased thanks to the fluoridation of the A ring. See also Anti-cancer Drug Design, (2001), 16, 27-36, for the substitution with chlorine in position 12.
The problem of the hydrosolubility of the homocamptothecins is addressed in U.S. Pat. No. 6,291,676, University of Kentucky, published on Sep. 18, 2001 with various substitutions of the (poly)alkylamine type in position 7.
However much in the design of new drugs various problems are encountered of a physicochemical nature, such as the stability of the molecule in plasma or its hydrosolubility for formulatory purposes, there is a constant search for a better therapeutic index.